Malignant phenotypes are driven by a group of coordinated proteins and targeting a cluster of functionally interdependent molecules should be more effective for therapeutic intervention. This is especially true for Ras- dependent cancers, as the Ras oncoprotein is non-druggable and targeting its interaction with key partner proteins may be essential for therapeutic development. K-Ras is mutated in up to 50% of colon cancers, and has been implicated in malignant development and progression. There is thus an urgent need to develop targeted therapies for K-Ras mutated (MT-K-Ras) colon cancer. This proposal will test the hypothesis that a p38g-activated ternary complex with MT-K-Ras and heat shock protein 90 (Hsp90) is a novel therapeutic target for K-Ras dependent colon cancer. This hypothesis is supported by our preliminary studies showing that p38g mitogen-activated protein kinase (MAPK), an established Ras effector, binds Hsp90, a chaperone, and MT-K-Ras, but not wild-type (WT) K-Ras, in colon cancer cells. Moreover, p38g phosphorylates Hsp90, and pharmacological inhibitors of p38g or Hsp90 disrupt the ternary complex, decrease MT-K-Ras levels of protein expression, and selectively inhibit K-Ras dependent growth in vitro and/or in vivo. Together, these results indicate that the p38g activated ternary complex with Hsp90 and MT-K-Ras is a potential therapeutic target for K-Ras dependent colon cancer. The following specific aims will test this hypothesis: 1) To demonstrate that p38g and Hsp90 form a ternary protein complex that protects MT-K-Ras from proteasome- dependent degradation; 2) To demonstrate if p38g activates Hsp90 by inducing its phosphorylation at S595 and whether this event is central to the formation of the MT-K-Ras/p38g/Hsp90 complex; and 3) To demonstrate the therapeutic potential and clinical significance of the p38g/Hsp90/K-Ras complex in colon cancer. These studies will demonstrate that the p38g-activated ternary-complex is a novel therapeutic target for MT-K-Ras colon cancer. Disruption of this complex with pharmacological inhibitors of p38g and Hsp90 is a highly promising therapeutic strategy for the treatment of K-Ras dependent colon cancer. Since colon cancer is the second leading cause of cancer-related death in the United States, discovery of novel targeted therapeutics for K-Ras dependent colon cancer will directly contribute to veteran's health care.